PINACOL PINACOLONE REARRANGEMENT ORGANIC CHEMISTRY

               
                
            
                  
                
                 
        

      

           

 

   

   

 

 

   

   

     

  

 

     

 

 

ANSEWR KEY
   B  C
   
2. 
 1.   

3. 4.

6.

    2.
 1. 


3. 4. 
P The pinacol rearrangement
Pinacol, the trivial name for the When the 1,2-diol ‘pinacol’ is treated with acid, a rearrangement takes place.
starting material, which is made
from acetone by a reaction you HO OH O
will meet in Chapter 39, gives its 2 H2SO4 4
1 3 4 1
2 Me pinacolone
name to this class of pinacol Me Me Me 3 70% yield
rearrangements, and to the Me Me Me
product, ‘pinacolone’. Me
Whenever you see a rearrangement, you should now think ‘carbocation’. Here, protonation of
one of the hydroxyl groups allows it to leave as water, giving the carbocation.

HO OH H HO OH2 HO
4
1 2 1 2 1 2 3 Me
3 4 3 4
Me Me Me Me Me
Me Me Me Me Me Me

You now know that carbocations rearrange by alkyl shifts to get as stable as they can be—but this
carbocation is already tertiary, and there is no ring strain, so why should it rearrange? Well, here we
P have another source of electrons to stabilize the carbocation: lone pairs on an oxygen atom. We
Unlike sulfur, which stabilizes a pointed out early in the chapter that oxygen is very good at stabilizing a positive charge on an adja-
charge 2 atoms away better than cent atom, and somewhat less good at stabilizing a positive charge two atoms away. By rearranging,
it stabilizes a charge on an
the first-formed carbocation gets the positive charge into a position where the oxygen can stabilize it,
adjacent atom.
and loss of a proton from oxygen then gives a stable ketone.
methyl H loss of a proton gives
oxygen's lone pair O a stable ketone O
HO migration 4
becomes involved, 4 4
3 Me 2 2 Me
stabilizing the new 1 2 1 Me 1
Me Me Me 3
positive charge 3 Me
Me Me Me
Me Me
You can view the pinacol as a rearrangement with a ‘push’ and a ‘pull’. The carbocation left by
the departure of water ‘pulls’ the migrating group across at the same time as the oxygen’s lone
pair ‘pushes’ it. A particularly valuable type of pinacol rearrangement forms spirocyclic ring
L systems. You may find this one harder to follow, though the mechanism is identical with that of
Spirocycles are pairs of rings joined at the last example. Our ‘top tip’ of numbering the atoms should help you to see what has happened:
a single carbon atom (Chapter 33).
atom 2 has migrated from atom 1 to atom 6.
O 9
5
10 P
OH OH10 + 1
4 9 H 6
8 Of course, it doesn’t matter how
5 green bond forms
black bond breaks you number the atoms, but the
1 6 7 numbering must be consistent.
3 8
4 2
2 7 Usually, your initial impression of
3 a greatly changed molecule will
When drawing the mechanism it doesn’t matter which hydroxyl group you protonate or which come down to just one or two
adjacent C–C bond migrates—they are all the same. One five-membered ring expands to a six-mem- atoms changing their substitution
pattern, and numbering will help
bered ring but the reason this reaction happens is the formation of a carbonyl group, as in all pinacol you to work out which ones they
rearrangements. are.
H
O O
OH OH2 OH
1 1 6
6
1 6
2 2 2
 The pinacol reaction in synthesis
A nice synthesis of the bicyclic alkene on the right starts with a pinacol reaction.

The first step is straightforward—just like the one you alcohol that rearranges to the alkene in acid. Try working
have just met. The ‘pinacol’ dimer from cyclobutanone out a mechanism for this transformation—start by
rearranges with the expansion of one of the rings to give a protonating of the alcohol and allowing water to leave to
cyclopentanone fused spiro to the remaining four- give a cation. You might also like to think about why the
membered ring. Reduction of the ketone then gives an rearrangement happens—for a clue go back to p. 000.
OH OH O HO
H+ reduce H+

pinacol
rearrangement
work out a mechanism for this step

Epoxides rearrange with Lewis acids in a pinacol fashion

The intermediate cation in a pinacol rearrangement can equally well be formed from an epoxide, and
treating epoxides with acid, including Lewis acids such as MgBr2, promotes the same type of reaction.
MgBr
O O Ph
MgBr2
OHC
Ph Ph Ph Ph
Ph
Rearrangement of epoxides with magnesium salts means that opening epoxides with Grignard
reagents can give surprising results.
R OH
1. RLi 1. RMgBr
2. H+ O 2. H+
OH R
The alkyllithium reaction is quite straightforward as long as the alkyllithium is free of lithium
salts. A clue to what has happened with the Grignard reagents comes from the fact that treating this
epoxide with just MgBr2 (no RMgBr) gives an aldehyde.
O
MgBr2 MgBr
O O MgBr CHO

With a Grignard reagent, rearrangement occurs faster than addition to the epoxide, and then the
Grignard reagent adds to the aldehyde.
With these symmetrical diols and epoxides, it does not matter which hydroxyl group is protonated
and leaves, nor which end the epoxide opens, nor which group migrates. When an unsymmetrical
diol or epoxide rearranges, it is important which way the reaction goes. Usually, the reaction leaves
behind the more stable cation. So, for example, this unsymmetrical diol gives the ring-expanded
ketone, a starting material for the synthesis of analogues of the drug methadone.
O Ph
OH Me
5 OH 1 Ph Ph
6 H2SO4 6
5 Ph
4 Ph NMe2 OEt
1 Ph 99% yield
4 2 methadone
3 2 3

This product is formed because the green OH group leaves more readily than the black because
the carbocation stabilized by two phenyl groups forms more readily than the carbocation stabilized
by two alkyl groups. The migration step follows without selectivity as both alkyl groups on the black
alcohol are the same.

OH OH OH Ph OH
OH OH

× × Ph
6 6 6 1
6 6
Ph 1 Ph Ph 1 Ph Ph
1 1 Ph
Ph Ph
2 2 2 2 2

this benzylic cation is more

stable and is formed faster formed
Which group migrates? (III)—stereochemistry matters too
Selectivity in rearrangement reactions is affected by the electronic nature of both the group that
migrates and the group that is left behind. But there is more! Stereochemistry is important too. The
outcome of diazotization and semipinacol rearrangement (Tiffeneau–Demjanov rearrangement) of
this amino-alcohol depends entirely on the diastereoisomer you start with. There are four
diastereoisomers, and we have drawn each one in the only conformation it can reasonably adopt,
with the t-butyl group equatorial.
O
NaNO2, HCl OH NaNO2, HCl
OH
NH2
90% yield 75% yield
CHO NH2
OH OH
NaNO2, HCl NaNO2, HCl
O
NH2
98% yield 77% yield
NH2

In all of these reactions, the OH group provides the electronic ‘push’. In the first two reactions,
the ring contracts by an alkyl migration from the secondary alcohol, while in the third it is H that
migrates from the same position.
alkyl group
migrates
OH
N2 H
H migrates O
CHO OH
alkyl group OH
migrates
H
N2
N2

The only difference between the compounds is stereochemistry and, if we look at the orbitals
involved in the reactions, we can see why this is so important. As the N2 leaving group departs, elec-
trons in the bond to the migrating group have to flow into the C–N σ* orbital—we discussed this on

Me
O
OH TsOH

OH
Me
OH OH
TsOH

HO O